Riluzole Prodrugs for Melanoma and ALS

描述（由申请人提供）：我们已经确定了一种新的利鲁唑IIb型前药FC-311，它有可能通过一种新的谷氨酸能作用机制来彻底改变治疗转移性黑色素瘤的破坏性疾病，也可用于治疗肌萎缩侧索硬化症（ALS）和利鲁唑本身正在临床评估的许多其他疾病。FC-311不像利鲁唑那样受Cyp1A2代谢的限制和大的患者间暴露变异性的影响，口服给药的寿命长3倍，生物利用度高，在黑色素瘤异种移植模型中表现出显著的剂量依赖性疗效。我们通过系统的体外和体内筛选策略，从30个候选药物中筛选出FC-311为最佳前药。我们已经最终证明FC-311不被Cyp1A2代谢，同时证实利鲁唑本身几乎完全被这种酶代谢，它在一般人群中具有不同的表达水平。我们已经实现了第一阶段研究计划的所有目标，并进行了许多最初没有描述或预期的额外研究。我们现在寻求II期支持，通过各种ind临床前开发活动推进FC-311。我们的目标是开发FC-311作为口服抗癌药物，以提供利鲁唑活性物质在患者之间的均匀递送。在目标1中，我们将进行原料药和化学相关的活动，通常被认为是任何药物发现和开发计划的一部分。这些工作包括制备300 g非gmp活性药物制剂，选择合适的盐形式、载体和配方，分析方法开发，原料药稳定性测试，评估额外的利鲁唑前药，以增加专利保护，作为备用，并可能考虑额外的适应症，继续对重要知识产权进行专利审查，以及制备5公斤FCC-311的cGMP。在Aim 2中，我们将继续必要的ind开发活动，包括完成代谢物ID研究（人类、大鼠和狗），确定与药效学相关的另外两种物种的完整PK参数，除了Cyp1A2缺失外，还研究Cyp450抑制作用，完成体外非glp毒理学研究（hERG、Ames、遗传毒性），在大鼠和狗身上进行28天的安全性药理学测试。以及FC-311进一步的辅助药理学测试。我们希望尽快向FDA提交IND，然后过渡到黑色素瘤患者的临床评估。我们已经建立了一个利鲁唑前药项目领导团队，由8名临床医生、药理学家和经验丰富的制药专家组成，以提供实时指导和支持，以确保该项目的成功。我们将申请FC-311治疗黑色素瘤的孤儿药指定，并寻求从风险投资和其他来源获得进一步的资金，或与一家大型制药公司合作，推进FC-311的临床开发的各个阶段。

DESCRIPTION (provided by applicant): We have identified a novel Type IIb prodrug of riluzole, FC-311, which has the potential to revolutionize therapy for the treatment of the devastating condition of metastatic melanoma acting via a novel glutamatergic mechanism of action, and also be useful to treat amyotrophic lateral sclerosis (ALS) and the many other conditions for which riluzole itself is under clinical evaluation. FC-311 is not subject to the limiting Cyp1A2 metabolism and large patient-to-patient variability of exposure that riluzole is, and has a ~3X longer high-life, higher bioavailability upon oral administration, and shows dramatic efficacy in a xenograft model of melanoma, in a dose dependent manner. We identified FC-311 as the optimal prodrug from among ~30 designed candidates using a systematic in vitro and in vivo screening strategy. We have demonstrated conclusively that FC-311 is not metabolized by Cyp1A2, while confirming that riluzole itself is metabolized nearly exclusively by this enzyme, which has variable levels of expression in the general population. We have achieved all of the aims of our Phase I program of study as well as conducted many additional studies that were not originally described or anticipated. We now seek Phase II support to advance FC-311 through various IND-enabling pre-clinical development activities. Our goal is to develop FC-311 as an oral anticancer agent in order to provide uniform, patient to patient delivery of riluzole active substance. In Aim 1, we will conduct drug substance and chemistry related activities normally considered as part of any drug discovery and development program. These include preparing 300 g of non-GMP active pharmaceutical agent, selection of suitable salt form, vehicle and formulation, analytical methods development, drug substance stability testing, evaluation of additional riluzole prodrugs for added patent protection, as back-ups, and for possible consideration for additional indications, continued patent prosecution of the important intellectual property involved, and preparation of 5 kg of cGMP of FCC-311. In Aim 2, we will continue the required IND-enabling development activities which include completion of metabolite ID studies (human, rat and dog), determination of full PK parameters in two additional species, correlated to pharmacodynamics, investigation of Cyp450 inhibition effect in addition to the demonstrated lack of Cyp1A2, completion of in vitro, non-GLP toxicology studies (hERG, Ames, genotoxicity), 28 day safety pharmacology testing in rats and dogs, and further ancillary pharmacology testing on FC-311. We wish to file an IND with the FDA as soon as possible, and then transition into clinical evaluation in melanoma patients. We have established a Riluzole Prodrug Project Leadership Team consisting of eight clinicians, pharmacologists and experienced pharmaceutical experts to provide real time guidance and support to ensure the success of this program. We will file for orphan drug designation for FC-311 for melanoma, and seek to obtain further funding from venture capital and other sources, or partner with a major pharmaceutical company, to advance FC-311 through the various phases of clinical development.